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Published on: November 5, 2021
Necroptosis does not drive disease pathogenesis in a mouse infective model of SARS-CoV-2 in vivo
Stefanie M Bader1,2, James P Cooney1,2, Reet Bhandari1,2
1The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.
Abstract:
Necroptosis, a type of lytic cell death executed by the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) has been implicated in the detrimental inflammation caused by SARS-CoV-2 infection. We minimally and extensively passaged a single clinical SARS-CoV-2 isolate to create models of mild and severe disease in mice allowing us to dissect the role of necroptosis in SARS-CoV-2 disease pathogenesis. We infected wild-type and MLKL-deficient mice and found no significant differences in viral loads or lung pathology. In our model of severe COVID-19, MLKL-deficiency did not alter the host response, ameliorate weight loss, diminish systemic pro-inflammatory cytokines levels, or prevent lethality in aged animals. Our in vivo models indicate that necroptosis is dispensable in the pathogenesis of mild and severe COVID-19.
Insights
Necroptosis, a cell death pathway involving Mixed Lineage Kinase Domain-Like (MLKL), does not significantly impact SARS-CoV-2 infection severity or outcomes in mouse models. These findings suggest necroptosis is dispensable in COVID-19 pathogenesis.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Necroptosis, a programmed lytic cell death, is mediated by Mixed Lineage Kinase Domain-Like (MLKL).
- Necroptosis has been suggested to contribute to the inflammation seen in SARS-CoV-2 infection.
- Understanding the role of necroptosis in COVID-19 pathogenesis is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of necroptosis in the pathogenesis of SARS-CoV-2 infection.
- To determine if MLKL-deficiency affects viral load, lung pathology, or disease severity in mouse models of COVID-19.
- To assess the impact of necroptosis on host response, inflammation, and lethality during SARS-CoV-2 infection.
Main Methods:
- Generation of mild and severe SARS-CoV-2 disease models in mice through varied passaging of a clinical isolate.
- Infection of wild-type and MLKL-deficient mice with SARS-CoV-2.
- Assessment of viral loads, lung pathology, host response, systemic cytokine levels, weight loss, and lethality.
Main Results:
- No significant differences in viral loads or lung pathology were observed between wild-type and MLKL-deficient mice.
- MLKL-deficiency did not alter host response, ameliorate weight loss, reduce systemic pro-inflammatory cytokines, or prevent lethality in aged mice with severe COVID-19.
- These in vivo findings indicate necroptosis is dispensable in both mild and severe COVID-19.
Conclusions:
- Necroptosis, executed by MLKL, is not a significant driver of pathogenesis in SARS-CoV-2 infection.
- MLKL-deficiency does not protect against SARS-CoV-2-induced pathology or lethality in mouse models.
- Targeting necroptosis may not be a viable therapeutic strategy for COVID-19.
